Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma
Document Type
Article
Publication Date
5-1-2018
Abstract
Despite novel therapies for melanoma, drug resistance remains a significant hurdle to achieving optimal responses. NRAS-mutant melanoma is an archetype of therapeutic challenges in the field, which we used to test drug combinations to avert drug resistance. We show that BET proteins are overexpressed in NRAS-mutant melanoma and that high levels of the BET family member BRD4 are associated with poor patient survival. Combining BET and MEK inhibitors synergistically curbed the growth of NRAS-mutant melanoma and prolonged the survival of mice bearing tumors refractory to MAPK inhibitors and immunotherapy. Transcriptomic and proteomic analysis revealed that combining BET and MEK inhibitors mitigates a MAPK and checkpoint inhibitor resistance transcriptional signature, downregulates the transcription factor TCF19, and induces apoptosis. Our studies demonstrate that co-targeting MEK and BET can offset therapy resistance, offering a salvage strategy for melanomas with no other therapeutic options, and possibly other treatment-resistant tumor types.
Identifier
85045707247 (Scopus)
Publication Title
EMBO Molecular Medicine
External Full Text Location
https://doi.org/10.15252/emmm.201708446
e-ISSN
17574684
ISSN
17574676
PubMed ID
29650805
Issue
5
Volume
10
Grant
P30CA010815
Fund Ref
National Institutes of Health
Recommended Citation
Echevarría-Vargas, Ileabett M.; Reyes-Uribe, Patricia I.; Guterres, Adam N.; Yin, Xiangfan; Kossenkov, Andrew V.; Liu, Qin; Zhang, Gao; Krepler, Clemens; Cheng, Chaoran; Wei, Zhi; Somasundaram, Rajasekharan; Karakousis, Giorgos; Xu, Wei; Morrissette, Jennifer J.D.; Lu, Yiling; Mills, Gordon B.; Sullivan, Ryan J.; and Benchun, Miao, "Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma" (2018). Faculty Publications. 8703.
https://digitalcommons.njit.edu/fac_pubs/8703
